The Canonical Transient Receptor Potential family of ion channel subunits comprise 7 distinct gene products (TRPC1-7), most of which are expressed in the central nervous system. Three subfamily members of this class (TRPC1, TRPC4, and TRPC5) are highly expressed in the hippocampus. These ion channel subunits forms homomeric and heteromeric channels with distinct characteristics. In addition, the currents mediated by these proteins are activated or potentiated by phospholipase C via subtypes of G protein-coupled receptors and tyrosine kinase receptors. In particular, Gq/11-linked receptors such as the type 1 metabotropic glutamate and M1, M3, and M5 muscarinic receptors, activate these currents by altering plasma membrane PIP2 and increasing intracellular Ca2+ concentrations. The function of the TRPC1/4/5 subfamily in hippocampus is not known. We hypothesize that hippocampal function is modulated by receptors that activate or potentiate these excitatory ion channels. We have generated mice lacking the TRPC4, TRPC5, both TRPC4 and TRPC5 genes, obtained the TRPC1 knockout mouse, and are breeding TRPC1/4/5 triple knockout mice. Here we propose to use these mice to understand the function of these ion channels in the hippocampus using protein localization, behavioral studies, acute brain slice recordings of hippocampus, and recordings of isolated hippocampal neurons. The results of these studies should clarify receptor-mediated alteration of hippocampal-mediated spatial and contextual memory, and identify new therapeutic targets for diseases and surgeries that affect the hippocampus.